Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN, also called Gastroenteropancreatic (GEP) neuroendocrine tumor and neuoroendocrine tumor (NET)) is the second most prevalent malignant tumor of the gastrointestinal (GI) tract in the U.S., more prevalent than gastric, esophageal, pancreatic, and hepatobiliary neoplasms, with an incidence of about 2.5-5 cases per 100,000. Incidence and prevalence have increased between 100 and 600 percent in the U.S. over the last thirty years, with no increase in survival.
Heterogeneity and complexity of GEP-NENs has made diagnosis, treatment, and classification difficult. These neoplasms lack several mutations commonly associated with other cancers; microsatellite instability is largely absent. See Tannapfel A, Vomschloss S, Karhoff D, et al., “BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors,” Am J Clin Pathol 2005; 123(2):256-60; Kidd M, Eick G, Shapiro M D, et al. Microsatellite instability and gene mutations in transforming growth factor-beta type II receptor are absent in small bowel carcinoid tumors,” Cancer 2005; 103(2):229-36. Individual histopathologic subtypes associate with distinct clinical behavior, yet there is no definitive, generally accepted pathologic classification or prediction scheme, hindering treatment development.
Existing diagnostic and prognostic approaches include imaging (e.g., CT and MRI), histology, and detection of some gene products. Available methods are limited, for example, by low sensitivity and/or specificity, and inability to detect early-stage disease. GEP-NENs often go undiagnosed until they are metastatic and often untreatable.
There is a need for specific and sensitive methods and agents for detection of GEP-NENs, including early-stage GEP-NENs, for example, for use in diagnosis, prognosis, prediction, staging, classification, treatment, monitoring, and risk assessment, and for investigating and understanding molecular factors of pathogenesis, malignancy, and aggressiveness of this disease. For example, such methods and agents are needed that can be performed simply, rapidly, and at relatively low cost. Provided herein are methods, compositions, and combinations that meet these needs.